The benefits of the Mediterranean diet (MedDiet) for type 2 diabetes (T2D) prevention were observed in epidemiologic studies and a randomized trial, yet the underlying mechanisms are not fully understood. Preliminary evidence indicates that a MedDiet is associated with gut microbial features favoring lower T2D risk. The gut microbiota, through producing biologically active molecular cues (e.g., metabolites and bacterial structural components), act on biological systems such as the host immune response and gut hormones (e.g., glucagon-like peptide-1) that underlie the pathogenesis of T2D. In addition, the high-polyphenol content of the MedDiet may interact with the gut microbiota to exert its health benefits because ingested polyphenols are mostly metabolized in the colon. To date, no study has investigated the potential mediating role of the gut microbiota in the association of the MedDiet with T2D. Most studies of the gut microbiota are cross-sectional studies or small short-term trials. For more advanced mechanistic insights, combining metagenomics, metatranscriptomics and metabolomics in an integrated framework presents a unique opportunity to probe the function of gut microbiota. Dr. Dong Wang will be mentored by an interdisciplinary team that includes Dr. Meir Stampfer, an expert in nutritional and chronic disease epidemiology, Dr. Curtis Huttenhower, a computational biologist who is a PI of NIH Integrative Human Microbiome Project, Dr. Andrew Chan, a gastroenterologist with expertise in population-scale microbiome study, and Dr. Wendy Garrett, an immunologist with expertise on biological function of gut microbiota. During the K99 phase, Dr. Wang will build on his expertise in nutritional epidemiology and metabolomics, and will be trained in human microbiome research, bioinformatics, and data mining the large multi-omics databases in a large cohort in Hispanic population. During the R00 phase, Dr. Wang will perform shotgun metagenomic and metatranscriptomic sequencing on repeatedly collected stool samples, and prospectively recruit participants to collect questionnaire data, blood and urine samples in a randomized controlled trial. The R00-phase research will test whether the gut microbiota modifies the long- term effects of the MedDiet and polyphenol-rich foods on T2D risk, and will examine the role of diet-induced gut microbial changes in regulating host immune homeostasis and gut hormone secretion. Findings from the proposed project will lead to novel mechanistic evidence on the health benefits of the MedDiet, which will have substantial public health impact by informing more effective and precision prevention of T2D. All of these will be possible through the use of an innovative study design and the functional profiling of gut microbiota by integrated ?omics and cutting-edge bioinformatic tools. The outstanding training opportunities with key leaders in research areas including gut microbiome, bioinformatics, translational research and nutritional interventions will greatly enhance the skills and capabilities of the candidate, and position him for a successful and independent career as a nutritional epidemiologist with expertise in gut microbiome and integrated ?omics.